PSA based screening has contributed to a dramatic increase in the number of prostate cancer cases and to a recent fall in mortality from the disease. However, this success has come at a cost: over-diagnosis and over-treatment for some and ineffectual treatment for others. Since upwards of 80% of men develop histologic prostate cancer, the critical question in 2004 is not who is at risk for developing prostate cancer, but who is at risk for developing lethal prostate cancer. Identification of those men at high risk for aggressive and potentially lethal prostate carcinoma prior to diagnosis would allow intense screening and/or prophylaxis while spading individuals at low risk years of screening. Identification of high risk patients at the time of diagnosis would target individuals for aggressive therapy while sparing those at low risk from potentially morbid treatment. Since it has been hypothesized that metastatic potential is determined at least in part by host genetic background, it follows that analysis of common polymorphic variants will prove to be a useful screening tool to determine who is at risk for lethal prostate carcinoma. We propose to perform a case control study to identify susceptibility loci for metastatic disease and then to validate our findings in additional cohorts including a prospectively acquired patient population. We have chosen genes in the cell cycle as our candidates because there are abundant data demonstrating 1) subtle genomic changes in cell cycle genes increase risk of cancer in animal models, 2) variants alter gene function in cell cycle genes and lastly 3) genetic variants within cell cycle genes are associated with aggressive prostate carcinoma. The three specific aims of this proposal are: (I) To search for associations between polymorphisms in cell cycle regulatory genes and increased risk of metastatic prostate carcinoma. (2) To determine if risk alleles identified in Aim 1 are predictors of metastatic prostate carcinoma specifically or prostate cancer in general by studying additional patient populations. (3) To establish a prospective cohort to determine if high risk SNPs are predictive of risk for treatment failure. At the conclusion of this study, we will have a panel of markers that can be used to predict which patients are at high risk of treatment failure and eventual death from prostate carcinoma.